Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents

ABSTRACT

Combinations of hydrophilic and hydrophobic entities in a biodegradable sustained release implant are shown to modulate each other&#39;s rate of release. Formulations of a therapeutically active agent and modulator provide substantially constant rate of release for an extended period of time.

TECHNICAL FIELD

[0001] Biodegradable implants formulated for controlled, sustained drugrelease.

BACKGROUND OF THE INVENTION

[0002] Solid pharmaceutically active implants that provide sustainedrelease of an active ingredient are able to provide a relatively uniformconcentration of active ingredients in the body. Implants areparticularly useful for providing a high local concentration at aparticular target site for extended periods of time. These sustainedrelease forms reduce the number of doses of the drug to be administered,and avoid the peaks and troughs of drug concentration found withtraditional drug therapies. Use of a biodegradable drug delivery systemhas the further benefit that the spent implant need not be removed fromthe target site.

[0003] Many of the anticipated benefits of delayed release implants aredependent upon sustained release at a relatively constant level.However, formulations of hydrophobic drugs with biodegradable matricesmay have a release profile which shows little or no release untilerosion of the matrix occurs, at which point there is a dumping of drug.

[0004] The eye is of particular interest when formulating implantabledrugs, because one can reduce the amount of surgical manipulationrequired, and provide effective levels of the drug specifically to theeye. When a solution is injected directly into the eye, the drug quicklywashes out or is depleted from within the eye into the generalcirculation. From the therapeutic standpoint, this may be as useless asgiving no drug at all. Because of this inherent difficulty of deliveringdrugs into the eye, successful medical treatment of ocular diseases isinadequate.

[0005] Improved sustained release formulations which allow for aconstant drug release rate are of considerable interest for medical andveterinary uses.

[0006] Relevant Literature

[0007] U.S. Pat. Nos. 4,997,652 and 5,164,188 disclose biocompatibleimplants for introducing into an anterior chamber or posterior segmentof an eye for the treatment of an ocular condition.

[0008] Heller, Biodegradable Polymers in Controlled Drug Delivery, in:CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 1, CRCPress, Boca Raton, Fla., 1987, pp 39-90, describes encapsulation forcontrolled drug delivery. Heller in: Hydrogels in Medicine and Pharmacy,N. A. Peppes ed., Vol. III, CRC Press, Boca Raton, Fla., 1987, pp137-149, further describes bioerodible polymers.

[0009] Anderson et al., Contraception (1976) 13:375 and Miller et al.,J. Biomed. Materials Res. (1977) 11:711, describe various properties ofpoly(dL-lactic acid). U.S. Pat. No. 5,075,115 discloses sustainedrelease formulations with lactic acid polymers and co-polymers.

[0010] Di Colo (1992) Biomaterials 13:850-856 describes controlled drugrelease from hydrophobic polymers.

SUMMARY OF THE INVENTION

[0011] Compositions and methods are provided for biodegradable implantsformulated to provide a controlled, sustained drug release. The releaserate is modulated by combining in the implant hydrophobic andhydrophilic agents. The release modulator may act to accelerate orretard the rate of release. Optionally, the modulator will be atherapeutically active agent. The invention provides a sustained releaseimplant having a combination of active agents with a defined releaseprofile.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1A shows the release profile of a hydrophobic drug from anextended release drug delivery system. FIG. 1B shows the release profileof the same drug when formulated in a drug delivery system with arelease modulator.

[0013]FIG. 2A shows the release profile of dexamethasone in the absenceor presence of the release modifier, ciproflaxacin HCl. FIG. 2B showsthe release of ciprofloxacin in the presence of dexamethasone. FIG. 2Cshows the release of ciprofloxacin in the absence of a release modifier.FIG. 2D shows the releae profile from a drug delivery system havingcombined hydrophilic and hydrophobic drugs, and further having apharmaceutically inactive release modifier.

[0014]FIG. 3 shows a cross-sectional view of an eye.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

[0015] A controlled drug release is achieved by an improved formulationof slow release biodegradable implants. The release rate of a drug froman implant is modulated by addition of a release modulator to theimplant. Release of a hydrophobic agent is increased by inclusion of anaccelerator in the implant, while retardants are included to decreasethe release rate of hydrophilic agents. The release modulator may bephysiologically inert, or a therapeutically active agent.

[0016] The rate of release of the therapeutically active agent will becontrolled by the rate of transport through the polymeric matrix of theimplant, and the action of the modulator. By modulating the releaserate, the agent is released at a substantially constant rate, or withina therapeutic dosage range, over the desired period of time. The rate ofrelease will usually not vary by more than about 100% over the desiredperiod of time, more usually by not more than about 50%. The agent ismade available to the specific site(s) where the agent is needed, and itis maintained at an effective dosage. The transport of drug through thepolymer barrier will also be affected by drug solubility, polymerhydrophilicity, extent of polymer cross-linking, expansion of thepolymer upon water absorption so as to make the polymer barrier morepermeable to the drug, geometry of the implant, and the like.

[0017] The release modulator is an agent that alters the release of adrug from a biodegradable implant in a defined manner. It may be anaccelerator or a retardant. Accelerators will be hydrophilic compounds,which are used in combination with hydrophobic agents to increase therate of release. Hydrophilic agents are those compounds which have atleast about 100 μg/ml solubility in water at ambient temperature.Hydrophobic agents are those compounds which have less than about 100μg/ml solubility in water at ambient temperature.

[0018] Therapeutically active hydrophobic agents which benefit fromrelease modulation include cyclosporines, e.g. cyclosporin A,cyclosporin G, etc.; vinca alkaloids, e.g. vincristine and vinblastine;methotrexate; retinoic acid; certain antibiotics, e.g. ansamycins suchas rifampin; nitrofurans such as nifuroxazide; non-steroidalantiinflammatory drugs, e.g. diclofenac, keterolac, flurbiprofen,naproxen, suprofen, ibuprofen, aspirin, etc. Steroids are of particularinterest, including hydrocortisone, cortisone, prednisolone, prednisone,dexamethasone, medrysone, fluorometholone, estrogens, progesterones,etc.

[0019] Accelerators may be physiologically inert, water solublepolymers, e.g. low molecular weight methyl cellulose or hydroxypropylmethyl cellulose (HPMC); sugars, e.g. monosaccharides such as fructoseand glucose, disaccharides such as lactose, sucrose, or polysaccharidessuch as cellulose, amylose, dextran, etc. Alternatively, the acceleratormay be a physiologically active agent, allowing for a combinedtherapeutic formulation. The choice of accelerator in such a case willbe determined by the desired combination of therapeutic activities.

[0020] Formulations of particular interest will have a therapeuticcombination of two or more active agents, which provides for a sustainedrelease of the agents. Combinations may include steroids, as indicatedabove, as the hydrophobic agent and water soluble antibiotics, e.g.aminoglycosides such as gentamycin, kanamycin, neomycin, and vancomycin;amphenicols such as chloramphenicol; cephalosporins, such as cefazolinHCl; penicillins such as ampicillin, penicillin, carbenicillin,oxycillin, methicillin; lincosamides such as lincomycin; polypeptideantibiotics such as polymixin and bacitracin; tetracyclines such astetracycline; quinolones such as ciproflaxin, etc.; sulfonamides such aschloramine T; and sulfones such as sulfanilic acid as the hydrophilicentity. A combination of non-steroidal anti-inflammatory drugs, asindicated above, with water soluble antibiotics is also of interest.Combinations of anti-viral drugs, e.g. acyclovir, gancyclovir,vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine withsteroidal or non-steroidal anti-inflammatory drugs, as indicated above,are of interest. A particular combination of interest is dexamethasoneand ciproflaxin.

[0021] Release retardants are hydrophobic compounds which slow the rateof release of hydrophilic drugs, allowing for a more extended releaseprofile. Hydrophilic drugs of interest which may benefit from releasemodulation include water soluble antibiotics, as described above,nucleotide analogs, e.g. acyclovir, gancyclovir, vidarabine,azidothymidine, dideoxyinosine, dideoxycytosine; epinephrine;isoflurphate; adriamycin; bleomycin; mitomycin; ara-C; actinomycin D;scopolamine; and the like.

[0022] Agents of interest as release retardants include non-watersoluble polymers, e.g. high molecular weight methylcellulose andethylcellulose, etc., low water soluble organic compounds, andpharmaceutically active hydrophobic agents, as previously described.

[0023] A combined anti-inflammatory drug, and antibiotic or antiviral,may be further combined with an additional therapeutic agent. Theadditional agent may be an analgesic, e.g. codeine, morphine, keterolac,naproxen, etc., an anesthetic, e.g. lidocaine; β-adrenergic blocker orβ-adrenergic agonist, e.g. ephidrine, epinephrine, etc.; aldosereductase inhibitor, e.g. epalrestat, ponalrestat, sorbinil, tolrestat;antiallergic, e.g. cromolyn, beclomethasone, dexamethasone, andflunisolide; colchicine. Anihelminthic agents, e.g. ivermectin andsuramin sodium; antiamebic agents, e.g. chloroquine andchlortetracycline; and antifungal agents, e.g. amphotericin, etc. may beco-formulated with an antibiotic and an anti-inflammatory drug. Forintra-ocular use, anti-glaucomas agents, e.g. acetozolamide, befunolol,etc. in combinations with anti-inflammatory and antimicrobial agents areof interest. For the treatment of neoplasia, combinations withanti-neoplastics, particularly vinblastine, vincristine, interferons α,β and γ, antimetabolites, e.g. folic acid analogs, purine analogs,pyrimidine analogs may be used. Immunosuppressants such as azathiprine,cyclosporine and mizoribine are of interest in combinations. Also usefulcombinations include miotic agents, e.g. carbachol, mydriatic agentssuch as atropine, etc., protease inhibitors such as aprotinin, camostat,gabexate, vasodilators such as bradykinin, etc., and various growthfactors, such epidermal growth factor, basic fibroblast growth factor,nerve growth factors, and the like.

[0024] The amount of active agent employed in the implant, individuallyor in combination, will vary widely depending on the effective dosagerequired and rate of release from the implant. Usually the agent will beat least about 1, more usually at least about 10 weight percent of theimplant, and usually not more than about 80, more usually not more thanabout 40 weight percent of the implant. The amount of release modulatoremployed will be dependent on the desired release profile, the activityof the modulator, and on the release profile of the active agent in theabsence of modulator. An agent that is released very slowly or veryquickly will require relatively high amounts of modulator. Generally themodulator will be at least 10, more usually at least about 20 weightpercent of the implant, and usually not more than about 50, more usuallynot more than about 40 weight percent of the implant.

[0025] Where a combination of active agents is to be employed, thedesired release profile of each active agent is determined. Ifnecessary, a physiologically inert modulator is added to preciselycontrol the release profile. The drug release will provide a therapeuticlevel of each active agent.

[0026] The exact proportion of modulator and active agent will beempirically determined by formulating several implants having varyingamounts of modulator. A USP approved method for dissolution or releasetest will be used to measure the rate of release (USP 23; NF 18 (1995)pp. 1790-1798). For example, using the infinite sink method, a weighedsample of the drug delivery device is added to a measured volume of asolution containing four parts by weight of ethanol and six parts byweight of deionized water, where the solution volume will be such thatthe drug concentration is after release is less than 5% of saturation.The mixture is maintained at 37° C. and stirred slowly to maintain theimplants in suspension. The appearance of the dissolved drug as afunction of time may be followed by various methods known in the art,such as spectrophotometrically, HPLC, mass spectroscopy, etc. until theabsorbance becomes constant or until greater than 90% of the drug hasbeen released. The drug concentration after 1 h in the medium isindicative of the amount of free unencapsulated drug in the dose, whilethe time required for 90% drug to be released is related to the expectedduration of action of the dose in vivo. Normally the release will befree of larger fluctuations from some average value which allows for arelatively uniform release, usually following a brief initial phase ofrapid release of the drug.

[0027] Normally the implant will be formulated to release the activeagent(s) over a period of at least about 3 days, more usually at leastabout one week, and usually not more than about one year, more usuallynot more than about three months. For the most part, the matrix of theimplant will have a physiological lifetime at the site of implantationat least equal to the desired period of administration, preferably atleast twice the desired period of administration, and may have lifetimesof 5 to 10 times the desired period of administration. The desiredperiod of release will vary with the condition that is being treated.For example, implants designed for post-cataract surgery will have arelease period of from about 3 days to 1 week; treatment of uveitis mayrequire release over a period of about 4 to 6 weeks; while treatment forcytomegalovirus infection may require release over 3 to 6 months, orlonger.

[0028] The implants are of dimensions commensurate with the size andshape of the region selected as the site of implantation and will notmigrate from the insertion site following implantation. The implantswill also preferably be at least somewhat flexible so as to facilitateboth insertion of the implant at the target site and accommodation ofthe implant. The implants may be particles, sheets, patches, plaques,fibers, microcapsules and the like and may be of any size or shapecompatible with the selected site of insertion.

[0029] The implants may be monolithic, i.e. having the active agenthomogenously distributed through the polymeric matrix, or encapsulated,where a reservoir of active agent is encapsulated by the polymericmatrix. Due to ease of manufacture, monolithic implants are usuallypreferred over encapsulated forms. However, the greater control affordedby the encapsulated, reservoir-type may be of benefit in somecircumstances, where the therapeutic level of the drug falls within anarrow window. The selection of the polymeric composition to be employedwill vary with the site of administration, the desired period oftreatment, patient tolerance, the nature of the disease to be treatedand the like. Characteristics of the polymers will includebiodegradability at the site of implantation, compatibility with theagent of interest, ease of encapsulation, a half-life in thephysiological environment of at least 7 days, preferably greater thantwo weeks, water insoluble, and the like. The polymer will usuallycomprise at least about 10, more usually at least about 20 weightpercent of the implant.

[0030] Biodegradable polymeric compositions which may be employed may beorganic esters or ethers, which when degraded result in physiologicallyacceptable degradation products, including the monomers. Anhydrides,amides, orthoesters or the like, by themselves or in combination withother monomers, may find use. The polymers will be condensationpolymers. The polymers may be cross-linked or non-cross-linked, usuallynot more than lightly cross-linked, generally less than 5%, usually lessthan 1%. For the most part, besides carbon and hydrogen, the polymerswill include oxygen and nitrogen, particularly oxygen. The oxygen may bepresent as oxy, e.g., hydroxy or ether, carbonyl, e.g.,non-oxo-carbonyl, such as carboxylic acid ester, and the like. Thenitrogen may be present as amide, cyano and amino. The polymers setforth in Heller, supra, may find use, and that disclosure isspecifically incorporated herein by reference.

[0031] Of particular interest are polymers of hydroxyaliphaticcarboxylic acids, either homo- or copolymers, and polysaccharides.Included among the polyesters of interest are polymers of D-lactic acid,L-lactic acid, racemic lactic acid, glycolic acid, polycaprolactone, andcombinations thereof. By employing the L-lactate or D-lactate, a slowlybiodegrading polymer is achieved, while degradation is substantiallyenhanced with the racemate. Copolymers of glycolic and lactic acid areof particular interest, where the rate of biodegradation is controlledby the ratio of glycolic to lactic acid. The most rapidly degradedcopolymer has roughly equal amounts of glycolic and lactic acid, whereeither homopolymer is more resistant to degradation. The ratio ofglycolic acid to lactic acid will also affect the brittleness of in theimplant, where a more flexible-implant is desirable for largergeometries.

[0032] Among the polysaccharides will be calcium alginate, andfunctionalized celluloses, particularly carboxymethylcellulose esterscharacterized by being water insoluble, a molecular weight of about 5 kDto 500 kD, etc. Biodegradable hydrogels may also be employed in theimplants of the subject invention. Hydrogels are typically a copolymermaterial, characterized by the ability to imbibe a liquid. Exemplarybiodegradable hydrogels which may be employed are described in Hellerin: Hydrogels in Medicine and Pharmacy, N. A. Peppes ed., Vol. III, CRCPress, Boca Raton, Fla., 1987, pp 137-149.

[0033] Particles can be prepared where the center may be of one materialand the surface have one or more layers of the same or differentcomposition, where the layers may be cross-linked, of differentmolecular weight, different density or porosity, or the like. Forexample, the center would comprise a polylactate coated with apolylactate-polyglycolate copolymer, so as to enhance the rate ofinitial degradation. Most ratios of lactate to glycolate employed willbe in the range of about 1:0.1 to 1:1. Alternatively, the center couldbe polyvinyl alcohol coated with polylactate, so that on degradation ofthe polylactate the center would dissolve and be rapidly washed out ofthe implantation site.

[0034] The formulation of implants for use in the treatment of ocularconditions, diseases, tumors and disorders are of particular interest.The biodegradable implants may be implanted at various sites, dependingon the shape and formulation of the implant, the condition beingtreated, etc. Suitable sites include the anterior chamber, posteriorchamber, vitreous cavity, suprachoroidal space, subconjunctiva,episcleral, intracorneal, epicorneal and sclera. Suitable sitesextrinsic to the vitreous comprise the suprachoroidal space, the parsplana and the like. The suprachoroid is a potential space lying betweenthe inner scleral wall and the apposing choroid. Implants that areintroduced into the suprachoroid may deliver drugs to the choroid and tothe anatomically apposed retina, depending upon the diffusion of thedrug from the implant, the concentration of drug comprised in theimplant and the like. Implants may be introduced over or into anavascular region. The avascular region may be naturally occurring, suchas the pars plana, or a region made to be avascular by surgical methods.Surgically-induced avascular regions may be produced in an eye bymethods known in the art such as laser ablation, photocoagulation,cryotherapy, heat coagulation, cauterization and the like. It may beparticularly desirable to produce such an avascular region over or nearthe desired site of treatment, particularly where the desired site oftreatment is distant from the pars plana or placement of the implant atthe pars plana is not possible. Introduction of implants over anavascular region will allow for diffusion of the drug from the implantand into the inner eye and avoids diffusion of the drug into thebloodstream.

[0035] Turning now to FIG. 3, a cross-sectional view of the eye isshown, illustrating the sites for implantation in accordance with thesubject invention. The eye comprises a lens 16 and encompasses thevitreous chamber 3. Adjacent to the vitreous chamber 3 is the optic partof the retina 11. Implantation may be intraretinal 11 or subretinal 12.The retina is surrounded by the choroid 18. Implantation may beintrachoroidal or suprachoroidal 4. Between the optic part of the retinaand the lens, adjacent to the vitreous, is the pars plana 19.Surrounding the choroid 18 is the sclera 8. Implantation may beintrascleral 8 or episcleral 7. The external surface of the eye is thecornea 9. Implantation may be epicorneal 9 or intra-corneal 10. Theinternal surface of the eye is the conjunctiva 6. Behind the cornea isthe anterior chamber 1, behind which is the lens 16. The posteriorchamber 2 surrounds the lens, as shown in the figure. Opposite from theexternal surface is the optic nerves, and the arteries and vein of theretina. Implants into the meningeal spaces 13, the optic nerve 15 andthe intraoptic nerve 14 allows for drug delivery into the centralnervous system, and provide a mechanism whereby the blood-brain barriermay be crossed.

[0036] Other sites of implantation include the delivery of anti-tumordrugs to neoplastic lesions, e.g. tumor, or lesion area, e.g.surrounding tissues, or in those situations where the tumor mass hasbeen removed, tissue adjacent to the previously removed tumor and/orinto the cavity remaining after removal of the tumor. The implants maybe administered in a variety of ways, including surgical means,injection, trocar, etc.

[0037] Other agents may be employed in the formulation for a variety ofpurposes. For example, buffering agents and preservatives may beemployed. Water soluble preservatives which may be employed includesodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate,phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethylalcohol. These agents may be present in individual amounts of from about0.001 to about 5% by weight and preferably about 0.01 to about 2%.Suitable water soluble buffering agents that may be employed are sodiumcarbonate, sodium borate, sodium phosphate, sodium acetate, sodiumbicarbonate, etc., as approved by the FDA for the desired route ofadministration. These agents may be present in amounts sufficient tomaintain a pH of the system of between 2 to 9 and preferably 4 to 8. Assuch the buffering agent may be as much as 5% on a weight to weightbasis of the total composition. Where the buffering agent or enhancer ishydrophilic, it may also act as a release accelerator, and may replaceall or part of the hydrophilic agent. Similarly, a hydrophilic bufferingagent or enhance may replace all or part of the hydrophobic agent.

[0038] The implants may be of any geometry including fibers, sheets,films, microspheres, circular discs, plaques and the like. The upperlimit for the implant size will be determined by factors such astoleration for the implant, size limitations on insertion, ease ofhandling, etc. Where sheets or films are employed, the sheets or filmswill be in the range of at least about 0.5 mm×0.5 mm, usually about 3-10mm×5-10 mm with a thickness of about 0.25-1.0 mm for ease of handling.Where fibers are employed, the diameter of the fiber will generally bein the range of 0.05 to 3 mm. The length of the fiber will generally bein the range of 0.5-10 mm. Spheres will be in the range of 2 μm to 3 mmin diameter.

[0039] The size and form of the implant can be used to control the rateof release, period of treatment, and drug concentration at the site ofimplantation. Larger implants will deliver a proportionately largerdose, but depending on the surface to mass ratio, may have a slowerrelease rate. The particular size and geometry of an implant will bechosen to best suit the site of implantation. The chambers, e.g.anterior chamber, posterior chamber and vitreous chamber, are able toaccomodate relatively large implants of varying geometries, havingdiameters of 1 to 3 mm. A sheet, or circular disk is preferable forimplantation in the suprachoroidal space. The restricted space forintraretinal implantation requires relatively small implants, havingdiameters from 0.5 to 1 mm.

[0040] In some situations mixtures of implants may be utilized employingthe same or different pharmacological agents. In this way, a cocktail ofrelease profiles, giving a biphasic or triphasic release with a singleadministration is achieved, where the pattern of release may be greatlyvaried.

[0041] Various techniques may be employed to produce the implants.Useful techniques include solvent evaporation methods, phase separationmethods, interfacial methods, extrusion methods, molding methods,injection molding methods, heat press methods and the like. Specificmethods are discussed in U.S. Pat. No. 4,997,652, herein incorporated byreference. In a preferred embodiment, extrusion methods are used toavoid the need for solvents in manufacturing. When using extrusionmethods, the polymer and drug are chosen so as to be stable at thetemperatures required for manufacturing, usually at least about 85° C.

[0042] The following examples are offered by way of illustration and notby way of limitation.

EXPERIMENTAL EXAMPLE 1 Manufacture and Testing of a Drug Delivery System(DDS) without a Release Modulator

[0043] Release of the hydrophobic drug dexamethasone from an extendedrelease drug delivery system was measured. The drug delivery system wasmade with dexamethasone and polylactic acid/polyglycolic acid copolymer.Dexamethasone powder and a powder of polylactic acid polyglycolic acid(PLGA) copolymer were mixed throughly at a ratio of 50/50. The wellmixed powder was filled into an extruder, and heated for 1 hour at 95°C., then extruded through a 20 gauge orifice. Six DDS of approximately100-120 μg were cut from the extruded filaments for drug releaseassessment.

[0044] Each individual DDS was placed in a glass vial filled withreceptor medium (9% NaCl in water). To allow for “infinite sink”conditions, the receptor medium volume was chosen so that theconcentration would never exceed 5% of saturation. To minimize secondarytransport phenomena, e.g. concentration polarization in the stagnantboundary layer, each of the glass vials was placed into a shaking waterbath at 37° C. Samples were taken for HPLC analysis from each vial atdefined time points. The HPLC method was as described in USP 23 (1995)pp. 1791-1798. The concentration values were used to calculate thecumulative relase profiles. The release profile is shown in FIG. 1A. Itis seen that drug release is very slow with this DDS. Appreciable drugrelease begins in the fourth week after initiation, at approximately thetime of polymer disintegration.

Manufacture and Testing of a DDS with HPMC Release Modifier

[0045] A drug delivery system was manufactured as described above,except that various concentrations of hydrophilichydroxypropylmethylcellulose (HPMC) were included as a release modifier.The combinations of drug, polymer and HPMC shown in Table 1 were used.TABLE 1 Lot # PLGA HPMC Dexamethasone Total XT014 3.5 1.5 5 10 XT015 2 25 9 XT013 1.5 1.5 5 8

[0046] The release of drug was tested as described above. The data isshown in FIG. 1B. It is seen that with the addition of HPMC, there is apronounced increase in the rate of release. Close to zero order releaseis observed for XT014 and XT015, where the ratio of release modulator todrug is 0.3 to 0.4. By selection of the appropriate polymer and releasemodifier, drug release and delivery interval can be custom-tailored toprovide a release profile that is accelerated or retarded.

EXAMPLE 2 Manufacture and Testing of a DDS with a PharmaceuticallyActive Release Modifier

[0047] A drug delivery system was manufactured as described in Example1, except that ciprofloxacin HCl, a pharmaceutically active, hydrophiliccompound, was included as a release modifier. The combinations of drug,polymer and HPMC shown in Table 2 were used. TABLE 2 Release Lot # PLGAModifier Drug XT029 5 — 5 dexamethasone XT032 4 2 ciprofloxacin 4dexamethasone XT030 5 — 5 ciprofloxacin

[0048] The release of dexamethasone is increased with the addition ofciprofloxacin HCl, as shown by the data in FIG. 2A. The actual drugrelease is almost doubled when compared to the DDS without a modifier.In addition to the benefits of increased drug delivery, there aretherapeutic benefits introduced with the antibiotic activity ofciprofloxacin. The release of ciprofloxacin from from the same DDS isshown in FIG. 2B. The release rate is higher than that of dexamethasone.However, the overall release of ciprofloxacin is slower whenco-formulated with dexamethasone than it is without dexamethasone, asshown in FIG. 2C.

EXAMPLE 3 Manufacture and Testing of a DDS with Multiple ReleaseModifiers

[0049] A drug delivery system was formulated withhydroxymethylcellulose, cirpofloxacin HCl and dexamethasone, accordingto the Table 3. TABLE 3 Lot # PLGA HPMC Ciprofloxacin DexamethasoneXT035 3.4 0.4 2.4 3.8

[0050] The data show that after an initial higher release in the firstday, an almost zero-order release there after can be observed. Theoverall release characteristic would be therapeutically acceptable froma therapeutic efficiency aspect.

[0051] It is evident from the above results that biodegradable implantsformulated with an active agent and release modulator provide forrelease kinetics where the drug is released at a constant rate over longperiods of time, avoiding the need of a patient to administer drugs inmuch less effective ways, such as topically. The implants provide animproved method of treating ocular and other conditions, by avoidingpeaks and troughs of drug release.

[0052] All publications and patent applications mentioned in thisspecification are indicative of the level of skill of those skilled inthe art to which this invention pertains. All publications and patentapplications are herein incorporated by reference to the same extent asif each individual publication or patent application was specificallyand individually indicated to be incorporated by reference.

[0053] Although the foregoing invention has been described in somedetail by way of illustration and example for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims.

What is claimed is:
 1. An implant for sustained drug release comprising:a pharmacologically acceptable biodegradable polymer which is degradedat the site of implantation, wherein said biodegradable polymercomprises at least about 20 weight percent of the implant; atherapeutically active agent at a concentration from 10 to 50 weightpercent of the implant; a release modulator at a concentration from 10to 50 weight percent of the implant; wherein said therapeutically activeagent is released within a therapeutic dosage which does not vary bymore than about 100% for a period of at least about 3 days.
 2. Animplant according to claim 1, wherein said release modulator is ahydrophilic entity and said therapeutically active agent is ahydrophobic entity.
 3. An implant according to claim 2, wherein saidrelease modulator is hydroxypropylmethylcellulose.
 4. An implantaccording to claim 1, wherein said release modulator is a hydrophobicentity and said therapeutically active agent is a hydrophilic entity. 5.An implant according to claim 1, wherein said release modulator is atherapeutically active agent.
 6. An implant according to claim 5,wherein said active agent is a steroid and said release modulator is awater soluble antibiotic.
 7. An implant according to claim 5, whereinsaid active agent is a non-steroidal antiinflammatory drug and saidrelease modulator is a water soluble antibiotic.
 8. An amplant accordingto claim 1, wherein said biodegradable polymer is poly-lactate glycolicacid copolymer.
 9. An implant for sustained drug release comprising:poly-lactate glycolic acid copolymer at a concentration of at leastabout 20 weight percent of the implant; methotrexate at a concentrationfrom 10 to 50 weight percent of the implant; ciprofloxin at aconcentration from 10 to 50 weight percent of the implant; wherein saidmethotrexate is released within a therapeutic dosage which does not varyby more than about 100% for a period of at least about 3 days.